Genetic Variant GSAP:p.Val723Leu (chr7-77314412-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017439.4(GSAP):c.2167G>T(p.Val723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V723M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

GSAP
NM_017439.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

Publications

0 publications found

Variant links:

Genes affected

GSAP (HGNC:28042): (gamma-secretase activating protein) Accumulation of neurotoxic amyloid-beta is a major hallmark of Alzheimer disease (AD; MIM 104300). Formation of amyloid-beta is catalyzed by gamma-secretase (see PSEN1; MIM 104311), a protease with numerous substrates. PION, or GSAP, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and its substrate, the amyloid-beta precursor protein (APP; MIM 104760) C-terminal fragment (APP-CTF) (He et al., 2010 [PubMed 20811458]).[supplied by OMIM, Nov 2010]

GSAP links:

CCDC146 (HGNC:29296): (coiled-coil domain containing 146) Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

CCDC146 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

CCDC146 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17573816).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017439.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSAP	NM_017439.4	MANE Select	c.2167G>T	p.Val723Leu	missense	Exon 27 of 31	NP_059135.2	A4D1B5-1
GSAP	NM_001350896.2		c.2167G>T	p.Val723Leu	missense	Exon 26 of 30	NP_001337825.1
GSAP	NM_001350897.2		c.2113G>T	p.Val705Leu	missense	Exon 26 of 30	NP_001337826.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSAP	ENST00000257626.12	TSL:1 MANE Select	c.2167G>T	p.Val723Leu	missense	Exon 27 of 31	ENSP00000257626.7	A4D1B5-1
GSAP	ENST00000441833.6	TSL:1	c.130G>T	p.Val44Leu	missense	Exon 4 of 8	ENSP00000415402.2	B7ZL33
GSAP	ENST00000491796.5	TSL:1	n.1613G>T		non_coding_transcript_exon	Exon 5 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0068

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.76

M_CAP

Benign

0.011

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.1

REVEL

Benign

0.15

Sift

Benign

0.085

Sift4G

Benign

0.27

Polyphen

0.98

Vest4

0.62

MutPred

0.34

Gain of helix (P = 0.2294)

MVP

0.30

MPC

0.37

ClinPred

0.76

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.085

gMVP

0.52

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over